Prospects for gene therapy to correct genetic disease or to deliver therapeutic molecules depend on the development of gene transfer vehicles that can safely deliver exogenous nucleic acid to a recipient cell. To date, most efforts have focused on the use of virus-derived vectors that carry a heterologous gene (transgene) in order to exploit the natural ability of a virus to deliver genomic content to a target cell.
For example, despite their reputation as major pathogenic agents that lead to numerous infectious diseases, adenoviruses (and particularly, replication-deficient adenoviruses) have attracted considerable recognition as highly effective viral vectors for gene therapy. Adenoviral vectors offer exciting possibilities based on their high efficiency of gene transfer, substantial carrying capacity, and ability to infect a wide range of cell types. Due to these desirable properties of adenoviruses, recombinant adenoviral vectors have been used for the cell-targeted transfer of one or more recombinant genes to diseased cells or tissue in need of treatment. In fact, adenovirus-based vectors offer several advantages, including tropism for both dividing and non-dividing cells, minimal pathogenic potential, ability to prepare vector stocks at high titer, and the potential to carry large DNA inserts. To date, genes that have been expressed by adenoviral vectors include p53, dystrophin, erythropoietin, ornithine transcarbamylase, adenosine deaminase, interleukin-2 and α-antitrypsin. Examples of adenovirus vectors can be found in U.S. Pat. No. 5,585,362 to Wilson et al., U.S. Pat. No. 5,824,544 to Armentano et al., and U.S. Pat. No. 5,846,782 to Wickham et al.
One barrier to successful gene transfer by viral vectors to patient hosts is the immune response of the host to the introduction of the virus. In terms of the general structure of an adenovirus, under the electron microscope, an adenovirus particle resembles a space capsule having protruding antennae. The viral capsid comprises at least six different polypeptides, including hexon, base and fiber proteins. The fiber, together with the hexon (Crawford-Miksza, L. and Schnurr, D. P., J. Virology, March 1996, pp. 1836-1844), determine the serotype specificity of the virus, and also comprise the main antigenic determinants of the virus.
This ability of adenoviral fiber and hexon protein to act as targets for a host immune response hamper attempts at adenoviral-mediated gene therapy. Namely, following adenoviral vector re-administration to prolong the therapeutic response, neutralizing antibodies develop against the adenoviral fiber and/or hexon proteins, thus circumventing adenoviral gene delivery to host cells. As the therapy is expensive, it is extremely wasteful to utilize a viral vector for gene therapy in a patient host that will mount an immune response to the vector.
What is needed is an efficient method of determining the likelihood that a patient host's immune system will interfere with intended gene therapy using viral vectors.